The role of Keap1-Nrf2 system in oxidative stress response of pancreatic β-cells

• Project/Area Number: 22890014
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: General medical chemistry
• Research Institution: Tohoku University
• Principal Investigator: URUNO Akira 東北大学, 大学院・医学系研究科, 助教 (90396474)
• Co-Investigator(Renkei-kenkyūsha): YAMAMOTO Masayuki 東北大学, 大学院・医学系研究科, 教授 (50166823)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥3,146,000 (Direct Cost: ¥2,420,000、Indirect Cost: ¥726,000); Fiscal Year 2011: ¥1,508,000 (Direct Cost: ¥1,160,000、Indirect Cost: ¥348,000); Fiscal Year 2010: ¥1,638,000 (Direct Cost: ¥1,260,000、Indirect Cost: ¥378,000)
• Keywords: Keap1-Nrf2システム / 糖尿病 / 酸化ストレス

Research Abstract

Nrf2 (NF-E2-related factor 2)is a basic region-leucine zipper-type transcription factor, which belongs to the Cap' n' collar family. Nrf2 is activated by various stresses including electrophiles, reactive oxygen species (ROS), reactive nitrogen species (RNS), and heavy metals, and coordinately induces anti-oxidant enzymes. Keap1 (Kelch-like ECH-associated protein 1)is an adaptor protein for Cullin3-base ubiquitin E3 ligase and acts as a sensor for stresses, which strictly regulates the Nrf2 activity.
We found that both Nrf2 and Keap1 are expressed in isolated islets from mice, and expression of Nrf2-target genes is upregulated by electrophiles, ROS and RNS. In addition, theβ-cell-damaged diabetes model mice crossed with Nrf2 hetero knockout showed elevated blood glucose levels and smaller islet size. Thus, these results support our contention that the Keap1-Nrf2 system plays important roles in the maintenance of pancreatic β-cells. The results further suggest that the Keap1-Nrf2 system may be involved in the pathogenesis of diabetes mellitus in stress conditions.

Research Products

• [Journal Article] Accumulation of p62/SQSTM1 is associated with poor prognosis in patients with lung adenocarcinoma (2012)
  • Author(s): Inoue D, Suzuki T, Mitsuishi Y, Miki Y, Suzuki S, Sugawara S, Watanabe M, Sakurada A, Endo C, Uruno A, Sasano H, Nakagawa T, Satoh K, Tanaka N, Kubo H, Motohashi H, Yamamoto M
  • Journal Title: Cancer Sci Volume: 103(4) Pages: 760-6
  • Peer Reviewed
• [Journal Article] Effects of PPAR γ agonists against vascular and renal dysfunction (2012)
  • Author(s): Sugawara A, Uruno A, Matsuda K, Funato T, Saito-Hakoda A, Kudo M, Ito S
  • Journal Title: Curr Mol Pharmacol Volume: (未定)(In press)
  • Peer Reviewed
• [Journal Article] The Keap1-Nrf2 system as an in vivo sensor for electrophiles (2011)
  • Author(s): Uruno A, Motohashi H
  • Journal Title: Nitric Oxide Volume: 25(2) Pages: 153-60
  • Peer Reviewed
• [Journal Article] All-trans retinoic acid and a novel synthetic retinoid tamibarotene (Am80)differentially regulate CD38 expression in human leukemia HL-60 cells : possible involvement of protein kinase C-δ (2011)
  • Author(s): Uruno A, Noguchi N, Matsuda K, Nata K, Yoshikawa T, Chikamatsu Y, Kagechika H, Harigae H, Ito S, Okamoto H, Sugawara A
  • Journal Title: J Leukoc Biol Volume: 90(2) Pages: 235-47
  • Peer Reviewed
• [Journal Article] Peroxisome proliferator-activated receptor-γ suppresses CYP11B2 expression and aldosterone production (2011)
  • Author(s): Uruno A, Matsuda K, Noguchi N, Yoshikawa T, Kudo M, Satoh F, Rainey WE, Hui XG, Akahira JI, Nakamura Y, Sasano H, Okamoto H, Ito S, Sugawara A
  • Journal Title: J Mol Endocrinol Volume: 46(1) Pages: 37-49
  • Peer Reviewed
• [Journal Article] 核内受容体および肝細胞増殖因子による血管応答機構の解明 (2011)
  • Author(s): 宇留野晃
  • Journal Title: 東北医学雑誌 Volume: 123 Pages: 203-206
  • NAID: 120006873306
  • Peer Reviewed
• [Journal Article] 膵β細胞におけるKeap1-Nrf2システムの役割 (2011)
  • Author(s): 宇留野晃
  • Journal Title: 日本応用酵素協会誌 Volume: 46 Pages: 90-90
• [Journal Article] All-trans retinoic acid and a novel synthetic retinoid tamibarotene (Am80) differentially regulate CD38 expression in human leukemia HL-60 cells: possible involvement of protein kinase C-{delta} (2011)
  • Author(s): Uruno A, Noguchi N, Matsuda K, Nata K, Yoshikawa T, Chikamatsu Y, Kagechika H, Harigae H, Ito S, Okamoto H, Sugawara A.
  • Journal Title: J Leukoc Biol Volume: 90 Issue: 2 Pages: 235-247
  • DOI: 10.1189/jlb.0109025
  • Peer Reviewed
• [Journal Article] 核内受容体および肝細胞増殖因子による血管応答機構の解明膵β細胞におけるKeap1-Nrf2システムの役割 (2011)
  • Author(s): 宇留野晃
  • Journal Title: 日本応用酵素協会誌 Volume: 46 Pages: 90-90
• [Journal Article] All-trans retinoic acid and a novel synthetic retinoid tamibarotene(Am80)differentially regulate CD38 expression in human leukemia HL-60 cells : possible involvement of protein kinase C-S (2011)
  • Author(s): Uruno A, Noguchi N, Matsuda K, Nata K, Yoshikawa T, Chikamatsu Y, Kagechika H, Harigae H, Ito S, OkamotoH, Sugawara A.
  • Journal Title: J Leukoc Biol. Volume: In press(未定)
  • Peer Reviewed
• [Journal Article] Peroxisome proliferator-activated receptor-γ suppresses CYPIIB2 expression and aldosterone production. (2011)
  • Author(s): Uruno A, Matsuda K, Noguchi N, Yoshikawa T, Kudo M, Satoh F, Rainey WE, Hui XG, Akahira JI, Nakamura Y, Sasano H, Okamoto H, Ito S, Sugawara A.
  • Journal Title: J Mol Endocrinol. Volume: 46 Pages: 37-49
  • Peer Reviewed
• [Journal Article] The Keapl-Nrf2 system as an in vivo sensor for electrophiles. (2011)
  • Author(s): Uruno A, Motohashi H.
  • Journal Title: Ncitric Oxide. Volume: In press(未定)
  • Peer Reviewed
• [Journal Article] Up-regulation of REG Iα accelerates tumor progression in pancreatic cancer with diabetes (2010)
  • Author(s): Zhou L, Zhang R, Wang L, Shen S, Okamoto H, Sugawara A, Xia L, Wang X, Noguchi N, Yoshikawa T, Uruno A, Yao W, Yuan Y
  • Journal Title: Int J Cancer Volume: 127(8) Pages: 1795-803
  • Peer Reviewed
• [Journal Article] チアゾリジン誘導体はPPARγおよびCa^<2+>/カルモジュリン依存性キナーゼ(CaMK)を介して副腎皮質癌H295R細胞におけるアルドステロン分泌を抑制する (2010)
  • Author(s): 宇留野晃、松田謙、野口直哉、吉川雄朗、工藤正孝、佐藤文俊、伊藤貞嘉、岡本宏、菅原明
  • Journal Title: ACTH related peptides Volume: 20 Pages: 36-37
• [Journal Article] レチノイド受容体によるPOMC転写調節機構 (2010)
  • Author(s): 宇留野晃、菅原明、松田謙、岩崎泰正、斉藤明子、工藤正孝、伊藤貞嘉
  • Journal Title: ACTH related peptides Volume: 20 Pages: 25-26
• [Journal Article] ストレスと生体反応. Nrf2-Keap1システムによるストレス応答制御 (2010)
  • Author(s): 宇留野晃、森口尚、山本雅之
  • Journal Title: Diabetes Frontier Volume: 21 Pages: 412-417
• [Journal Article] PPARγと生活習慣病 (2010)
  • Author(s): 菅原明、宇留野晃、松田謙、工藤正孝、伊藤貞嘉
  • Journal Title: ホルモンと臨床 Volume: 58 Pages: 143-148
• [Journal Article] PPARγによるCYP11B2およびアルドステロン分泌調節機構の検討 (2010)
  • Author(s): 宇留野晃
  • Journal Title: 日本応用酵素協会誌 Volume: 45 Pages: 101-102
• [Journal Article] Up-regulation of REG I α accelerates tumor progression in Pancreatic cancer with diabetes. (2010)
  • Author(s): Zhou L, Zhang R, Wang L, Shen S, Okamoto H, SugawaraA, Xia L, Wang X, Noguchi N, Yoshikawa T, Uruno A, Yao W, Yuan Y.
  • Journal Title: Int J Cancer. Volume: 127 Pages: 1795-1803
  • Peer Reviewed
• [Journal Article] ストレスと生体反応～Nrf2-Keaplシステムによるストレス応答制御～ (2010)
  • Author(s): 宇留丑晃、森口尚、山本雅之
  • Journal Title: Diabetes Frontier Volume: 21 Pages: 412-417
• [Presentation] 膵β細胞におけるKeap1-Nrf2システムの役割 (2011)
  • Author(s): 宇留野晃、柳下陽子、菅原明、山本雅之
  • Organizer: 第77回日本生化学会東北支部会例会
  • Place of Presentation: 仙台
  • Year and Date: 2011-07-23
• [Presentation] Effects of Retinoid X Receptor on ACTH Secretion and POMC Gene Expression in AtT20 Corticotroph Cells (2011)
  • Author(s): Uruno A, Matsuda K, Kudo M, Iwasaki Y, Ito S, Sugawara A
  • Organizer: The Endocrine Society 93rd Annual Meeting
  • Place of Presentation: ボストン、アメリカ合衆国
  • Year and Date: 2011-06-23
• [Presentation] Differential effects among ARBs on aldosterone synthase (CYP11B2) gene expression in human adrenal H295R cells (2011)
  • Author(s): Matsuda K, Uruno A, Kudo M, Satoh F, Ito S, Sugawara A
  • Organizer: The Endocrine Society 93rd Annual Meeting
  • Place of Presentation: ボストン、アメリカ合衆国
  • Year and Date: 2011-06-23
• [Presentation] Relationship between Silent Brain Infarction and Primary Aldosteronism (2011)
  • Author(s): Matsuda K, Uruno A, Kudo M, Satoh F, Ito S, Sugawara A
  • Organizer: 35th Meeting of the International Aldosterone Conference
  • Place of Presentation: ボストン、アメリカ合衆国
  • Year and Date: 2011-06-22
• [Presentation] Differential effects among ARBs on aldosterone synthase (CYP11B2) gene expression in human adrenal H295R cells (2011)
  • Author(s): Kudo M, Satoh F, Morimoto R, Iwakura Y, Ono Y, Murakami O, Matsuda K, Sugawara A, Uruno A, Takase K, Ito S
  • Organizer: 35th Meeting of the International Aldosterone Conference
  • Place of Presentation: ボストン、アメリカ合衆国
  • Year and Date: 2011-06-22
• [Presentation] Effects of Retinoid X Receptor on ACTH Secretion and POMC Gene Expression in AtT20 Corticotroph Cells (2011)
  • Author(s): Uruno A, Matsuda K, Kudo M, Iwasaki Y, Ito S, Sugawara A
  • Organizer: The Endocrine Society 93rd Annual Meeting
  • Place of Presentation: Boston
  • Year and Date: 2011-06-04
• [Presentation] Differential effects among ARBs on aldosterone synthase (CYP11B2)gene expression in human adrenal H295R cells (2011)
  • Author(s): Matsuda K, Uruno A, Kudo M, Satoh F, Ito S, Sugawara A
  • Organizer: The Endocrine Society 93rd Annual Meeting
  • Place of Presentation: Boston
  • Year and Date: 2011-06-04
• [Presentation] 基本的血液検査データを用いたパターン認識手法に基づくクッシング症候群の早期診断支援システムの開発 (2011)
  • Author(s): 工藤正孝、佐藤文俊、青木空眞、森本玲、岩倉芳倫、小野美澄、松田謙、村上治、宇留野晃、菅原明、佐藤憲一、伊藤貞嘉
  • Organizer: 第84回日本内分泌学会学術総会
  • Place of Presentation: 神戸
  • Year and Date: 2011-04-23
• [Presentation] 各アンジオテンシンII受容体拮抗薬(ARB)はアルドステロン合成酵素(CYP11B2)発現に異なる影響を及ぼす (2011)
  • Author(s): 松田謙、宇留野晃、工藤正孝、佐藤文俊、伊藤貞嘉、菅原明
  • Organizer: 第84回日本内分泌学会学術総会
  • Place of Presentation: 神戸
  • Year and Date: 2011-04-22
• [Presentation] Role of heparan sulfate in glucose-induced insulin secretion in MIN6 cells (2010)
  • Author(s): Yoshikawa T, Takayanagi S, Noguchi N, Uruno A, Okamoto H, Sugawara A, Yanai K
  • Organizer: American Diabetes Association 70th Scientific Sessions
  • Place of Presentation: Orlando
  • Year and Date: 2010-06-25
• [Presentation] Role of heparan sulfate in glucose-induced insulin secretion in MIN6 cells. (2010)
  • Author(s): Yoshikawa T, Takayanagi S, Noguchi N, Uruno A, Okamoto H, Sugawara A, Yanai K.
  • Organizer: American Diabetes Association 70th Scientific Sessions.
  • Place of Presentation: Orlando USA
  • Year and Date: 2010-06-23
• [Book] レチノイン酸受容体(RAR)によるPOMC遺伝子発現における転写因子NeuroD1およびTpitの役割, 平成22年度総括・分担研究報告書 (2011)
  • Author(s): 宇留野晃、菅原明、松田謙、工藤正孝、岩崎泰正、伊藤貞嘉
• [Book] レチノイドX受容体(RXR)がACTH分泌・POMC遺伝子発現に及ぼす影響に関する検討, 平成21年度総括・分担研究報告書 (2010)
  • Author(s): 宇留野晃、菅原明、岩崎泰正、伊藤貞嘉
• [Remarks]
  • URL: http://www.dmbc.med.tohoku.ac.jp/
• [Patent(Industrial Property Rights)] 糖尿病の予防または治療剤 (2012)
  • Inventor(s): 山本雅之、宇留野晃、古澤祐樹
  • Industrial Property Rights Holder: 国立大学法人東北大学, 持田製薬株式会社
  • Industrial Property Number: 2012-072990
  • Filing Date: 2012-03-28